NM_000059.4(BRCA2):c.7931A>G (p.Asn2644Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 5, 2022
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000162644.11

Allele description [Variation Report for NM_000059.4(BRCA2):c.7931A>G (p.Asn2644Ser)]

NM_000059.4(BRCA2):c.7931A>G (p.Asn2644Ser)

Gene:

BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.7931A>G (p.Asn2644Ser)

HGVS:

NC_000013.11:g.32362648A>G
NG_012772.3:g.52169A>G
NM_000059.4:c.7931A>GMANE SELECT
NP_000050.2:p.Asn2644Ser
NP_000050.3:p.Asn2644Ser
LRG_293t1:c.7931A>G
LRG_293:g.52169A>G
LRG_293p1:p.Asn2644Ser
NC_000013.10:g.32936785A>G
NM_000059.3:c.7931A>G
U43746.1:n.8159A>G
p.N2644S

Nucleotide change:

8159A>G

Protein change:

N2644S

Links:

dbSNP: rs80359020

NCBI 1000 Genomes Browser:

rs80359020

Molecular consequence:

NM_000059.4:c.7931A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

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mothers against decapentaplegic homolog 3 isoform 4 [Homo sapiens]
mothers against decapentaplegic homolog 3 isoform 4 [Homo sapiens]
gi|223029444|ref|NP_001138576.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000213081	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Jan 5, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000906944	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 5, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31131967, 31780696, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000213081

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Jan 5, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV000906944

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 5, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Classifying Variants of Undetermined Significance in BRCA2 with protein likelihood ratios.

Karchin R, Agarwal M, Sali A, Couch F, Beattie MS.

Cancer Inform. 2008;6:203-16. Epub 2008 Apr 18.

PubMed [citation]

PMID:: 19043619
PMCID:: PMC2587343

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.

Parsons MT, Tudini E, Li H, Hahnen E, Wappenschmidt B, Feliubadaló L, Aalfs CM, Agata S, Aittomäki K, Alducci E, Alonso-Cerezo MC, Arnold N, Auber B, Austin R, Azzollini J, Balmaña J, Barbieri E, Bartram CR, Blanco A, Blümcke B, Bonache S, Bonanni B, et al.

Hum Mutat. 2019 Sep;40(9):1557-1578. doi: 10.1002/humu.23818.

PubMed [citation]

PMID:: 31131967
PMCID:: PMC6772163

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000213081.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000906944.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces asparagine with serine at codon 2644 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 31780696) and in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0246 and 0.6533, respectively (PMID: 31131967). This variant has been identified in 1/251308 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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